Docetaxel (trade name: Taxotere) is a synthesized compound after structural modification extracted from Taxus baccata leaves, a white or almost white crystalline powder, with molecular formula C43H53NO14, chemical name: [2aR-(2aα,4β,4aβ,6β,9α,(αR*,βS*),11α,12α,12aβ,12bα)]-β-[[(1,1-dimethyl ethoxy) carbonyl]amino]-α-hydroxyphenyl propionic acid [12b-acetoxy-12-benzoyloxy-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxyl-4-a,8,13,13-tetramethyl-5-oxo-7,11-methylene-1H-pentacyclo-ene[3,4]benzo[1,2-b]tetraoxacyclo-9-base]acetate trihydrate. Its molecular weight is 807.19. This product is a new taxus anti-tumor drug, belongs to a fat-soluble compound, difficult to dissolve in water (2.903 μg/ml). Because the benzoyl group of the paclitaxel is substituted by t-butoxycarbonyl, the water-solubility of Docetaxel is slightly larger than that of Paclitaxel (0.25 μg/ml˜0.60 g/ml).
The anti-tumor mechanism of this product is the same as that of paclitaxel, which exerts its anti-tumor activity by inhibiting tubulin depolymerization. However, its inhibitory activity of tubulin depolymerization is about 2 times of that of paclitaxel, so it has a better curative effect on advanced breast carcinoma, superior to other single drug therapy (25%-53%) and stronger than anthracyclines, with an effective ratio of 49% for treatment of advanced breast carcinoma and better curative effects on advanced non-a-cell lung cancer, advanced ovarian cancer, pancreatic cancer, head and neck cancer and gastric cancer.
Docetaxel is insoluble in water and other commonly used medicinal organic solvent. It is used as injection in clinical application, and its injection solution is prepared with docetaxel Tween solution (injection specification: 1 ml, 20 mg/ml) and 13% ethanol and normal saline or glucose. The tween solution has a lower stability, stored at a low temperature of 2˜8° C. in a dark place. The injection solution for clinical use is easily to precipitate. This product has similar side effects as paclitaxel, which may cause serious allergic reactions after injection, and the incidence rate of moderate and severe hypersusceptibility is as high as 25.9% (Onconlogy, 1997, 11 (7): 11); If the dosage is 75 mg/m2 or 100 mg/m2, the incidence rate of moderate hypersusceptibility or more is respectively 31% and 41.3% and the injection-part reaction rate can also be up to 13.3% (Cancer, 1995, 754:968). Therefore, when docetaxel is used, allergic reaction prevention treatment should be conducted by taking large doses of hormones from PM8:00 on the first day before the docetaxel treatment, generally taking dexamethasone 4.5 mg orally, once in the morning and once at night every day, for 3˜5 days in succession; 30 min-60 min before injection of docetaxel, intramuscular injection of 40 mg diphenhydramine and 300 mg cimetidine were conducted to prevent from hypersensitivity. To prevent gastrointestinal reaction, intravenous injection of ondansetron or Nasea shall be conventionally conducted 30 min prior to chemotherapy. In addition, it is quite troublesome for clinical use of docetaxel, closely observing whether there are leaks or not in the process of fluid infusion; if any, the injection part must be immediately replaced and local blocking should be conducted with Hirudoid ointment for external use (3 times per day, for a few days). In addition, the conventional ECG monitoring should be carried out to closely observe the changes of breathing, heart rate and blood pressure, pay close attention to the occurrence of allergic reactions and make sure a good preparation of care rescue for severe allergic reactions. At present, improving the stability of docetaxel formulations and reducing the side effects become the focus of technical difficulties.
In recent years, researches on paclitaxel formulations mainly focus on liposomes, nano-granule, albumin cross-linked precursor, cyclodextrin inclusion and so on. The key technology focuses on biocompatibility, in vivo tolerance of the selected materials, paclitaxel solubilization and formulation stability, Similar to paclitaxel, for the docetaxel formulation improvement, the cyclodextrin inclusion technology is increasing widely used, and acet-γ-cyclodextrin, Hydroxypropyl-β-cyclodextrin and 2,6-dimethyl-β-cyclodextrin have been reported to use for docetaxel modification. Current study showed that application of cyclodextrin inclusion technology can not only enhance docetaxel stability, enhance its solubility, but also can significantly enhance the drug activity and reduce toxic and side effects. By using methyl-β-cyclodextrin/docetaxel inclusion and other drugs to determine their effects on the activity of a wide range of tumor cells IC50 (European Journal of Cancer, 1998, 34: 168-174), it was discovered that, after adding methyl-β-cyclodextrin, docetaxel IC50 CD was significantly reduced and IC50/IC50 CD values f different cells were within the scope ranging from 4.7-14.3, which proved that, cyclodextrin inclusion can significantly enhance the activity of docetaxel. The inclusion formulations made of acet-β-cyclodextrin or hydroxypropyl-β-cyclodextrin (WO9924073; CN1222321/ZL 98811010.5) can significantly reduce toxic and side effects of cardiovascular and respiratory system, but preferable technical solution in the invention is to prepare the composition with docetaxel/hydroxypropyl-β-cyclodextrin in a mass ratio of 1:133, the solubility of docetaxel is 0.75 mg/ml; if with the docetaxel/acetyl-γ-cyclodextrin in a mass ratio 1:50; the solubility of docetaxel can be up to 1.00 mg/ml, despite of increased docetaxel solubility, but each dose specification (20 mg) of docetaxel injection solution prepared by such technology still require not less than 1 ml ethanol as a cosolvent. If the existing technology is used to conduct cyclodextrin/docetaxel inclusion, which would be unable to meet the drug requirements for clinical use, the main problem is: The solubility of docetaxel after cyclodextrin inclusion is still relatively low, inconvenient for clinical use (need substantial solvent) and difficult to meet the suitable dosage requirements; application of substantial cyclodextrin will seriously affect practical applications; solubilization of inclusion with high doses of organic solvent can not only be conducive to cyclodextrin solubilization, but also increase the formulation irritation and reduce the patient's compliance. In aspect of technical methods, current technology only focuses on pharmaceutical stability of formulations (clarification/precipitation of the solution), while ignoring the drug chemical stability of especially for in the solution. Because cyclodextrin has the features of catalyzing ester compounds (Organic Chemistry, 2002; 22 (11):827-834), docetaxel containing ester-based side chains in solution could tend to stabilize due to cyclodextrin inclusion, or accelerate decomposition by cyclodextrin catalysis (cause decrease of stability). The inclusion is directly related to the stability and cyclodextrin structural property (type of cyclodextrin). These factors caused difficult extended application of current technology. Therefore, less use of cyclodextrin and no use or less use of organic solvents for improving the docetaxel solubility to meet the dose requirements of clinical application and maintaining the drug pharmaceutical nature and chemical stability are the technical problems for use of cyclodextrin inclusion technology in docetaxel.
At present, the cyclodextrin and cyclodextrin derivatives used to injection only include α-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin only (Expert Opin Drug Deliv, 2005 March; 2 (2): 335-51), among of which, hydroxypropyl-β-cyclodextrin is a neutral non-ionized derivative and sulfobutyl-β-cyclodextrin is an ionized derivative. Studies shows that (Medicine Forefront, Chinese Medicine Science and Technology Press, 2001: 46-59), sulfobutyl-β-cyclodextrin was significantly improved in safety, stability, drug solubilization and production preparation technology, etc. Recently, we researched and developed a new type of cyclodextrin derivative-hydroxypropyl-sulfobutyl-3-cyclodextrin (CN 1800221A), which has excellent performance and good safety. In the present invention, hydroxypropyl-sulfobutyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin was used to improve docetaxel. The low proportion (mass ratio 1:17) of inclusion can promote the docetaxel solubility up to 15 mg/ml or higher. The prepared injection has a good pharmaceutical property and chemical stability, strong activity and low irritation. If the solid inclusion was diluted for 500 times, it can maintain stable for several days, with an important clinical application value.